Therapeutic composition

ABSTRACT

A therapeutic composition comprised of an aqueous medium containing about 75-150 millimoles of Na , about 5-50 millimoles of K , about 5-50 millimoles of HCO3 , about 75-150 millimoles of Cl and preferably containing about 1-30 millimoles of Mg and about 1-30 millimoles of HPO4 and/or SO4 ; the solution having a pH of about 6.8-8.2 and an osmolality of about 170-460 and preferably about 260-340 and more preferably 290-310. The solution can be administered orally but preferably parenterally. Also, the anhydrous form of the composition in a tablet form as well as an oral composition containing flavoring agents is taught.

United States Patent Reynolds 1 [451 July 11, 1972 [54] THERAPEUTIC COMPOSITION [72] Inventor: Beverly L. Reynolds, Dallas, Tex.

[73] Assignee: Cybersol, Inc., Dallas, Tex.

[22] Filed: Dec. 15, 1969 [21] Appl. No.: 885,295

[52] U.S. Cl ..424/128, 424/153, 424/ l 54, I 424/ 162 [51] Int. Cl. ..A6lk 27/00 [58] Field ot'Search ..424/l28, 153,180, 154,162

[56] References Cited UNITED STATES PATENTS 233,063 10/1880 Boughton ..424/l28 2,265,453 12/1941 Schmidt ..424/128 2,224,252 12/1940 Callaway ..99/l

Polli et al ..424/ l 53 Butcher ..424/ l 53 [5 7] ABSTRACT A therapeutic composition comprised of an aqueous medium containing about 75-150 millimoles of Na", about 5-50 millimoles of 1?, about 5-50 millimoles of HCO about 75-150 millimoles of Cland preferably containing about 1-30 millimoles of Mg and about l-30 millimoles of HPOF and/or SQ the solution having a pH of about 6.8-8.2 and an osmolality of about 170-460 and preferably about 260-340 and more preferably 290-310. The solution can be administered orally but preferably parenterally. Also, the anhydrous form of the composition in a tablet form as well as an oral composition containing flavoring agents is taught.

11 Claims, No Drawings BACKGROUND OF THE INVENTION After accidental or elective operative injury to human patients, there occurs a decrease in the hemoglobin concentration, an elevation of the erythrocyte sedimentation rate of peripheral blood, and a loss of red blood cells (RBC) from the effective blood volume. These events are recognized as anemia. Also, immediately subsequent to the injury the white solution has enhanced water retention significantly, as evidenced by consistent gain in weight during operation when saline is administered. complimenting normal saline solutions with potassium and calcium in concentrations equivalent to plasma water mEq/L, total) has had little additional effect. Hence, the addition of ions to sterile water in quality and at concentrations approximately those in blood water has not significantly reduced anemias observed from the use of sterile water alone.

cell count is usually elevated, and the thrombocyte count is 10 Examples of parenterally administrable preparations in curdecreased, implicating pancytic mechanisms.

rent USC are:

Approx- Gluimate Phos- Aceeon- Lac- Solution pH Na K Mg Ca C1 phate H003 tate ate tate Human plasma." 7.4 140 45 2-3 5 102 2.5 2.7 5 NormosolR pH 7.4 140 5 3 9 Lactated Ringer's 6.5 Normal saline... 5. 4 Dextrose 5% in 4. 6 ysal 6.2 Plasma-Ly te 6. 2

Cations (meqJL) Anions (meq./l.)

1 Trademark of Abbott Laboratories, North Chicago, Illinois. Trademark of Cutter Laboratories, Berkeley 10, California. 3 Trademark of Baxter Laboratories, Inc., Mortln Grove, Illinois.

The administration of whole blood is useful to rectify the pancytic changes. However, most surgeons have been unable to maintain adequate quantities of peripheral total hemoglobin, red blood cells, and thrombocytes through the use of whole blood, even when quantities far in excess of that lost by bleeding are infused. Also, the collection and storage of whole blood generally produces a hyperosmolar, acidic water solution, as a result of the changes in RBC and blood water during collection and storage. Furthermore, whole blood is expensive, and may produce unwanted immunohematological responses in the recipient.

The surgeon and anesthesiologist generally have four other choices, i.e., instead of whole blood infusion, to correct these adversities. These are administration of (l) plasma, (2) separated (packed) erythrocytes, (3) synthetic water solutions, or (4) synthetic water solutions containing synthetic protein. Plasma has some of the disadvantages of whole blood. Separated erythrocytes, besides being expensive, have the disadvantage of decreases in functional and structural life after reinfusion. In recent years, synthetic water solutions, with or without protein, have been used to re-establish normalcy in peripheral vascular volumes and for maintenance of blood pressure.

The development of synthetic water solutions in the prior art has emphasized ionic content, particular sodium chloride, with little regard to other physicochemical requirements. Such thinking is still current. The most recently introduced water solutions beg their use through ionic contents equivalent to plasma water as the latter appears during health. Also, the blood water of patients, receiving a multitude of new anesthetic agents and adjuvants and subjected to operative techniques of increasing complexity, is exposed to body water infusates which are at variance, frequently extreme, with the physicochemical content in health.

Altering ionic content of water solutions has not provided the water environment considered optimal during elective or traumatic operative therapy. Furthermore, synthetic water solutions should provide support to the patient in excess of maintenance of blood water volume. Water for injection, sterile, U.S.P., may be used to replace or expand blood water lost during elective or accidental trauma, if the sole purpose of administered water solution is the replacement of water losses. However, the anemia or injury is more intense in the postoperative period after use of sterile water or of other similar hypo-osmolar solutions, resulting in prolonged morbidity, particularly in post-operative hospital time, and accounting for the more frequent use of whole blood before, during, and after operation.

The addition of sodium chloride to sterile water, in so-called isotonic concentration (154 mEq/L [milliequivalents/liter]), has reduced only minimally the post-operative anemia. Such a Certain of these solutions are compared in specific tests with applicant's aqueous solution.

SUMMARY OF THE INVENTION Applicant has discovered a therapeutic composition, preferably administered parenterally, to overcome at least most of the disadvantages of similar aqueous solutions in the prior art. The formulation is based on the mean solute values in extracellular water (referred to herein as ECW) and is designed to minimize water movements into fixed cells after operative, anesthetic and accidental trauma. Also, Applicants parenteral solution diminishes loss of functional decrements in all body systems, particularly heart and circulating fluids, lung, kidney, gastrointestinal tract and brain. Applicants composition is useful in tablet form, oral dosage form containing flavoring agent, etc.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Applicants therapeutic composition is preferably isoosmolar with respect to the mean osmolality of ECW. The mobility of the ions is preferably maximal in the ECW to minimize ICW (intracellular water) depletion or overload. Also, the water content is preferably representative of the ratio of water to solute loss during the operative procedure or trauma or imbalance.

In extracellular water, the major cations are H, K, Na", Ca, and Mg whereas the major anions are OH, HCO Cl, S0 HPOf, and IDA (impermeable organic anions). The relative size of the hydrated ions, as referenced to K*, and the velocity of each ion in water, in a uniform electrical field, are:

The mobility coefficient of each ion in dilute water solution is dependent upon the size of the hydrated ion and upon its velocity under a uniform electrical gradient. Changes in solute content, pH, and osmolality affect the mobility coefficients. The Mg, HPOf and S0,, ions are implicated as components of intercellular water or interstitial water substrates during glycolysis and oxidative reaction sequences in energy metabolism.

Applicants parenteral solution contains sodium (Na and potassium (K*) as the principal major cation solutes, and bicarbonate (HCO and chloride (Cl') as the primary anion solutes. These were selected because their coefficients of mo bility, with hydrogen (H*) and hydroxyl (OH), are maximal with respect to all other solutes, in any given situation. Magnesium (Mg was selected as the principal minor solute cation, and phosphate (HPO4 and/or sulfate (50 as the principal minor solute cation. The Mg, HPOF and 50; ions assist in stabilization of solute velocities, hence distribution, in the extracellular water and/or the intercellular water. The concentration of the ions in applicant's aqueous solution are given in millimoles as:

Min- Max- Pre- Most Ion imum imum ferred Preferred Sodium (Na*) 75 150 85-140 128 Potassium (K*)5 50 10-40 17 Magnesium (Mg**) 1 30 2-20 5 Phosphate (HPOf, ,1 30 2-20 Sulfate (SOP,

Bicarbonate (HCO; 5 50 -40 25 Chloride (Cl) 75 150 85-130 120 The administrable solution can have an osmolality (defined as the specific number of millimoles dissolved in one liter of water) within the range of from about 170 to about 460, preferably from 260 to 340, more preferably from 290 to 310 and most preferably about 300. The pH can range from about 6.8 to 8.2 and preferably is within the range of 7.4 to 8.0 and more preferably about 7.6 to about 7.8. It is not necessary that the Mg, SO4 and HPOF be present but it is preferred where stabilization of solute velocities, thus distribution, is desired in the ECW and/or ICW. Known water soluble salts containing the above ions are useful to make up the solution in U.S.P. water. Examples of such salts include NaCl, KCl, NaH- CO KHCO MgCl Na SO Na HPO MgSO,, and H- PO,.

A preferred composition for parenteral administration is one containing about 25 millimoles of NaHCO about 17 millimoles of KCl, about 103 millimoles of NaCl and about 5 millimoles of MgSO Solutions having an osmolality less than about 290 can be designed to move into the cells; thus, such solutions are useful in treatment of heat stroke or situations causing excessive sweating. However, if the osmolality desired is in excess of about 310, the solution can be designed to attract water out of the cells. As a result, such solutions are useful, for example, in the treatment of overdoses of barbiturates or any situation resulting in an unusual accumulation of water within the cells.

The pH of the solution is desirably about 6.8 to about 8.2. Such pH is preferably obtained by using the appropriate salts taught within this invention and such solution will be highly buffered against pH changes. Adjustment of the pH can be obtained, if desired, with known acids or bases, e.g., HCL, NaOH, etc. whose reactions with the solution will not produce ion solutes different from those specified.

The solution is preferably administered parenterally; but, it can be administered orally. Where oral administration is desired, the salt components are desirably chosen to eliminate objectionable taste of the solution. For example, KCl can impart a bad taste. A more acceptable solution from the standpoint of taste is one containing KHCO NaHCO MgCl and Na SO,. Flavoring agents, e.g., orange flavoring, etc. and

pharmaceutically acceptable vitamins in dosage form compatible with applicants composition can be incorporated. For example, vitamin C is useful where the solution is taken orally. Other additives pharmaceutically acceptable and compatible with applicants composition can also be incorporated.

Also, the appropriate amount of cations and anions can be contained in the anhydrous form as well as a concentrated hydrous form. The hydrous form can be at a concentration more than the desired osmolality and, before administration, it can be diluted to the desired osmolality. By containing the solution at a high ion concentration, shipping charges, storage costs, etc. can be reduced.

Regarding the anhydrous form, the appropriate salts and the desired amounts of salts can be contained in a protective container (a pharmaceutically acceptable container) so that convenient dilution to the desired volume and at the desired place of usage can be obtained. Also, the salts can be compressed in a uniform mixture and can optionally contain an inert diluent, e.g., binder. Thus, the salts can be embodied in a tablet suitable for dilution and eventually oral administration.

The tablet binder is a pharmaceutically acceptable binder and is preferably one that produces minimum osmotic effects and is one that is not ionized. Examples of useful binders include nonionic detergents such as Pluronic F-68 (trademark of Wyandotte Chemicals Corp., defined as a condensate of ethylene oxide with a condensate of propylene oxide and propylene glycol) and similar nonionic detergents, preferably having molecular weights above about 8,000. Also, the tablet can contain pharmaceutically acceptable effervescent agents such as citric acid, tartic acid, etc. Where the salts are in the anhydrous form, the concentration of the ions can be (mole 70):

Where the Mg and HPOf and/or SO; ions are absent, the molar composition can be about 37.546.9% Na about 3.1-l2.5% K", about 3.l-12.5% HCO and about 46.9-37.5% Cl. But, preferably, the Mg and HPOf and/or SO,- are present.

Applicants solution is preferably administered to mammals before operation, during anesthesia, during operation and after operation or trauma. Desirably, it is administered in quantities calculated to replace water and osmolar losses in the ECW. Excessive administration of the solution can be tolerated by the mammal, however, over-expansion of the ECW can modify moble cell mobilization. Preferably, the solution is administered before trauma and in amounts calculated to replace water and osmolar losses in the ECW. Where administered before operation and before anesthesia, it is preferably begun about 2 hours prior to anesthesia.

Proper administering of applicants solution, inter alia, can have the following benefits:

1. iso-osmolar expansion of ECW with predictable equilibration of administered water between circulating water volume and lSW space components of ECW;

2. as a result of( l a high tolerance of unplanned overloading of the circulating water volume-thus hypertension, cardiac pulmonary failure and coma can be reduced;

3. as a result of (1), maintenance of suspension indices of solutes, e.g., mobile cells, lipids, and proteins, in ECW is obtained;

4. as a result of( l and (3), iso-osmolar expansion of large solutes in ECW is obtained;

5. as a result of (4), minimization of mobile cell destruction (particularly red cell) and of intravascular aggregation of cells is obtained-both of which otherwise follow planned or unplanned trauma;

All solutions were prepared on the day of use after careful weighing of dried reagents and addition of sterile water for injection, U.S.P., to 1,000 milliliters. Sterilization was accomplished by autoclave, after which a 5-milliliter aliquot of each as a resfult of (l)t enhancemem of Perfusion of {issues 5 was removed and analyzed for solute content, osmolality, pH 8 electlvei PPeTatlVe, and aflesthetlc trauma, wlth or and sterility. After evaluation, ligatures were removed, inciwithout P accidental P i redueedsions closed, and animals returned to their cages.

Other benefits are obvious after the specification and claims are read and fully understood. Deprivation Tests T f0 owing examples are preseined 'P teach Fifteen canines to each of five series were observed dunng specific working embodiments of the invention. Equivalents and uses obvious to those skilled in the art ar int d d t b water depnvanon of the ECW by hemorrhage at 47 percent of t d th d f e e the TBV. In one series, no replacement water solution was adz 6 mven as e me m t e spec ministered, and, as reported in Table I, no animals survived 24 [on an appen c alms hours; these animals expiring secondary to cardiac and pulmonary arrest. In four additional series, Applicants solution EXAMPLE (USP. water containing 25 millimoles of Nat-[C0 17 mil- Mongrel canines having a mean weight f 15 kgm were limoles of KCL, 103 millimoles of NaCl and 5 millimoles of operated on under pentobarbital sodium anesthesia for bi- 8 4 osmolality 300 pH 7.6 7.8) and certain other lateral placement of ligatures about the renal pelvi and/or for 20 water Solutlons were infused singly P the canines at the Spleneetemy Seven days after operation, these animals were onset of ventricular fibrillationand cardiac arrest. The infused exposed to either water loading or water deprivation test, as quantities were equal to the Shed blood Volume slfl'vwal was indicated below. The aoric blood pressure, the hematocrit 100 P ammals reeelvmg pp wlth a (HCT), blood water volume 31w and extraeellular water mobilization of an additional 16 percent of RBC. Survwai was volume (ECW) were determined before and after either loadreduced markedly in all animals receiving other water ing or deprivation, and at indicated times. Where a control pati ns. Regarding other water solutions, enhancement of TBV tient is used, neither loading nor deprivation was efi'ected and was best With Sodium Chloride, but P and RBC decreases a lapse of time equal to the same lapse for either loading or contributed to low survival. Similarly, pH and RBC alterations deprivation was allowed for the after determination. Where by other water solutions decreased survival. Furthermore, loading experiments were done, minutes was allowed 30 there is no statistical difference between animals receiving between the determinations. In depletion experiments, detereither no water replacement or either lactated Ringers soluminations were made immediately after hemorrhage, at 2 tion or Normosol-R. These results are reported in Table 1. hours past hemorrhage, and at 5 days past hemorrhage. The TABLEI BlW was measured with T-1824 dye, also defined as Evans blue dye; 30 minutes was allowed for equilibration of the dye. Comparison of applicants solution with other water solu- HCT was determined from multiple arterial and venous tions (all values 1 hour after replacement of water solution microhematocrit determinations (corrected for trapped equal 120 Shed blood Volume) TABLE I Condition TBV .IIG'I RBC BlW ISW ECW Percent mortality, 24 hours Steady suite before deprivation 1, 050 44 465 585 2, 670 3, 720 47%lnnnorrlnigo 555 31 165 390 2, 590 3,145 100, W/O water replacement.

53 35 62 93 85 Aiterupplicunts solution 800 31 235 565 2, 840 3, 640 Zero (0%).

pll 7.6 76 51 97 106 98 300 mOJL.

After sodium chloride 820 18 148 672 2,912 3, 732 80.

30s mO./L.

Aiterlactated Ringer's and/or Normosol-R 570 23 150 420 3,639 4, 209 90.

260 mO./L.

After polysal and/or Plastma-Lite 615 26 160 455 3,030 3, 645 75.

pH 6.7 58 34 vs 114 98 *Percent of steady state.

*mO./L. mi1lim0les/liter. v F w H V, V V i, i plasma) and was related to the true or total body he- Effect of Varying Osmolalities of Applicants Solution During matocrit by the ratio 0.85-this ratio was empirically mea- Water Deprivation Sured by comparing direct red cell Volume and blood Water Table Ii indicates the effect of varying the osmolality of apmeasurements in 25 canines. Red cell mass (RBC) was calculicants solutions (pH 6.8-8.2) upon the mortality of lated from the hematocritand blood water volume. was canines after water deprivation through hemorrhage of measuredwlth radlobromlum, EH 2, E was allowed for percent of steady state TBV. A 47 percent hemorrhage was equlllbfatlon of the e p lmel'smlal water W35 sufficient to produce death in 100 percent of the canines in detel'mlffed as the dlffel'enee between and the absence of injection of parenteral fluids. The replacement Osmolalrty was determined by commercial osmometer. f li l i i equal to h d m d;

Specific gravities of all water solutions either added or TABLE II removed were determined, thus specific correlations were Osmolality of in- Mor- RBC Mass after infusion established between the weight of either added or removed fused solution tam}, Percent f TBv after fluids. The partial pressure of water vapor in the ambient air (millimoles/liter) percent 47% Hemorrhage was adjusted to the partial pressure of water vapor in the expired air of the animal under evaluation. During loading, the ligatures were tightened about the renal pelvi. Therefore, after 310 Zero 4,0 the 30 mmute interval for distribution of added water solu- 300 Zero +15 tions, during the 2 hours allowed for equilibration of isotope 290 g" and 30 minutes for equilibration of the dye, water losses from i I the animals were minimized.

The above data clearly indicates basis for preferred osmolality ranges, especially the 290-310 range.

each produced dislocations of water and solutes and reduction in RBC as compared to applicants solution (identified in Water Loading" tests, osmolality 300).

Establishment of pH Range Five canines to each of 10 series were observed during TABLEV separate water deprivation tests of hemorrhage of 47 percent Condition Blood of TBV. The exact quantity of shed TBV was replaced at the 323 gle cqg Pre zuie lBIW onset of cardiac arrest with sodium chloride and sodium bicar- Aortic Femoral 2 3 bonate mixtures at pH in range of from 5.5 to 8.8 although these solutions are not the same as applicants solution, these Water loading data obtained are applicable with their invention. The critical (7 of TBV) pH established with minimum mortality, i.e., no mortality, is 10 l 25 from 6.8to 8.2. I H 35 Water Loading 1 5 Waiter Depri Each of canines in three different series were observed qgc zzi gg during water loading with (1) aqueous solutions of sodium hemorrhage) chloride, (2) aqueous solutions of sodium bicarbonate and (3) 10 2.0 2 'II' fN H- 3 12-25 4 applicant 5 aqueous solution containing m1 m0 es 0 a 5 O 60 9 5 CO 17 millimoles of KCl, 103 millimoles of NaCl and 5 mil- 20 b 77 limoles of MgSO The mean ECW of the canine 3,000 ml. 47 9 3 99 18 Results of the tests are given in Table Ill:

TABLE III Water solution administered ECW after infusion ICW RBC mass Percent Percent Percent TBV percent increase change water increase or water osmolality volume decrease mO./L. volume mO./L. ECW

Volume, Total, ml.

A. Aqueous solution of sodium chloride 600 3, 610 20. 3 0. 66 298 0 Decrease 5.2.

( 00 3, 605 20 0. 299 0 Decrease iLZ.

(300 3, 798 20. 6 1. 66 295 0. 6 Decrease 6.4.

B. Aqueous solution of sodium bicarbonate 600 3, 625 20. 8 0. 71 297 0 Decrease 1.6.

600 3, 056 21. 5 +0.15 302 0 Increase ;l:l.5.

000 3, 710 23. 4 +0.15 301 3. 6 Decrease 3.3.

C. Applicant's aqueous solution 300 600 3, 600 20 0 300 0 Increase 20.

The above data indicate that with applicant's solution the Eff t n Blood Pres ure with Applicants Solution ECW was expanded by the same increment as the load and there was neither an increase nor decrease in osmolality. Also, 45 During water loading and water deprivation tests, the effect the RBC component of TBV was increased by same percentage as was the ECW, hence BIW was expanded in identical manner, 20 percent, such that TBV was increased 20 percent.

Comparison with Other Water Solutions During Loading on the aortic and femoral blood pressures were observed. Results of these tests are indicated in Table V. Applicants aqueous solution is identical to the one identified in Water- Loading tests.

- Applicant's solution was compared with other water solutions at 30 minutes after canine water loading. The loading Loading at Diff Osmolalities and pH was equal to 100 percent of TBV. Data are presented in Table t IV: Loading of ECW with applicant s solution at different TABLE IV Percent Mortality Condition TBV HCT RBC BIW lSW ECW n24 hours Steady State Before 1100 44 485 615 3900 5000 Loading AllcrApplicant's 1320 44 585 735 4800 6l20 Zero Solution +20 +20 +20 +23 +20 pH 7.6 300 mO/L After Sodium Chloride H 37 435 725 5300 6460 0 pH5.5308mO/L +5 17 17 +18 +36 +29 (Normal saline) Aflcrlnctatcd Ringer's H35 37 432 703 49I5 6050 Zero and/or NormosoI-R pH 6.5 200 mO/l. After Polysul And/or H28 39 440 788 4932 6060 Zero llnsmal-Lyte +3 ll ll 28 27 22 pH 6.7 280 mO/l.

"r ot'Stendy State,

The above data indicate that with sodium chloride, the RBC was reduced 17 percent, and 20 percent of the canines exosmolalities and pH was effected. The loading was equal to 100 percent of TBV. The infused solutions contain Na", K*,

pired. The other solutions produced no mortality, however, Cl and HCO; as the primary components and Mg, HPO,

and 80 as minor components (3-10 millimoles) at the indicated osmolalities and pH. Results are indicated in Table Vl:

What is claimed is:

I. An injectable acqueous solution comprising about 75 to about 150 millimoles of sodium cation, about 5 to about 50 millimoles of potassium cation, about 5 to about 50 millimoles of bicarbonate anion and about 75 to about 150 millimoles of chloride anion and having a pH of about 6.8 to about 8.2 and an osmolality of about 290 to about 310.

2. The composition of claim 1 wherein the pH is about 7.4 to about 8.0.

3. The composition of claim 1 wherein the osmolality is about 300.

4. The composition of claim 1 wherein about 1 to about 30 millimoles of magnesium cation and from about 1 to about 30 millimoles of phosphate and/or sulfate anion are incorporated into the composition.

5. The aqueous solution of claim 1 wherein there is incorporated about 1 to about 30 millimoles of magnesium cation.

6. The aqueous solution of claim 1 wherein there is incorporated about I to about 30 millimoles of phosphate anion or sulfate anion or a combination of phosphate and sulfate anions.

7. The aqueous solution of claim 1 wherein the osmolality is about 300. I

8. The aqueous solution of claim 1 wherein the pH of the solution is about 7.4 to about 8.0.

9. An injectable aqueous solution comprised of about 85 to about 140 millimoles of sodium cation, about 10 to about 40 millimoles of potassium cation, about 2 to about 20 millimoles of magnesium cation, about 85 to about 130 millimoles of chloride anion, about 10 to about 40 millimoles of bicarbonate anion and about 2 to about 20 millimoles of phosphate and/or sulfate anion(s) and the solution having a pH within the range of about 6.8 to about 8.2 and having an osmolality within the range of about 290 to about 310.

10. The aqueous solution of claim 9 wherein the pH is within the range of about 7.4 to about 8.0.

11. An injectable aqueous solution comprised of about 103 millimoles of sodium chloride, about 25 millimoles of sodium bicarbonate, about 17 millimoles of potassium chloride, and about 5 millimoles of magnesium sulfate and having a pH within the range of about 7.6 to about 7.8. 

2. The composition of claim 1 wherein the pH is about 7.4 to about 8.0.
 3. The composition of claim 1 wherein the osmolality is about
 300. 4. The composition of claim 1 wherein about 1 to about 30 millimoles of magnesium cation and from about 1 to about 30 millimoles of phosphate and/or sulfate anion are incorporated into the composition.
 5. The aqueous solution of claim 1 wherein there is incorporated about 1 to about 30 millimoles of magnesium cation.
 6. The aqueous solution of claim 1 wherein there is incorporated about 1 to about 30 millimoles of phosphate anion or sulfate anion or a combination of phosphate and sulfate anions.
 7. The aqueous solution of claim 1 wherein the osmolality is about
 300. 8. The aqueous solution of claim 1 wherein the pH of the solution is about 7.4 to about 8.0.
 9. An injectable aqueous solution comprised of about 85 to about 140 millimoles of sodium cation, about 10 to about 40 millimoles of potassium cation, about 2 to about 20 millimoles of magnesium cation, about 85 to about 130 millimoles of chloride anion, about 10 to about 40 millimoles of bicarbonate anion and about 2 to about 20 millimoles of phosphate and/or sulfate anion(s) and the solution having a pH within the range of about 6.8 to about 8.2 and having an osmolality within the range of about 290 to about
 310. 10. The aqueous solution of claim 9 wherein the pH is within the range of about 7.4 to about 8.0.
 11. An injectable aqueous solution comprised of about 103 millimoles of sodium chloride, about 25 millimoles of sodium bicarbonate, about 17 millimoles of potassium chloride, and about 5 millimoles of magnesium sulfate and having a pH within the range of about 7.6 to about 7.8. 